Our previous studies to date in the etiology of hepatic encephalopathy have documented significant abnormalities in a category of neurotransmitter or neurom dulators, which may control, in part, the level of alertness or underlie the level of activity of the brain, specifically, the catecholamine, serotonin, betahydroxyphenylethylamine neurotransmitter modulating system. Previous studies have documented abnormalities in these neuromodulators, including decreased norepinephrine, increased serotonin and increased betahydroxyphenylethylamine. These in turn appear related to abnormalities in the brain concentrations of the precursor neutral amino acid, particularly phenylalanine, tyrosine and tryptophan, which in turn appear related to abnormalities in the large neutral amino acid group in the plasma, particularly elevated phenylalanine, tyrosine, free but not total tryptophan, valine, leucine, and isoleucine. The principal agency controlling the relationship between the plasma concentration and the brain concentration of these various large neutral amino acids is the blood brain barrier. Several years ago, studies pointed to the blood brain barrier as being abnormal. These studies have approached it in two ways. The first is direct measurement of the brain uptake index in experimental animals, and the second by the calculation from the plasma concentration of the predicted brain concentrations of the amino acid neurotransmitter precursors. Several lines of evidence have recently pointed to at least two distinct mechanisms by which these abnormalities in the brain take place. The first is the decreased competition, secondary to the relationship between the plasma concentrations of the various neutral amino acids; the second implies exchange for glutamine. This period of the grant will be devoted to further defining the relationship between these two competitive mechanisms, and some of the mechanisms underlying the abnormality in the blood brain barrier. Another aspect of the grant involves the causation of a metabolic, hepatic-like coma by the infusion of various amino acids into awake, conditioned dogs with exteriorized carotid artery loops. To date, phenylalanine and tryptophan, two amino acids alone, have been shown as being capable of causing a grade IV unresponsive hepatic encephalopathy with EEG similarities to hepatic encephalopathy. The infusion of both tryptophan and ph (Text Truncated - Exceeds Capacity)